Biomedical subjects

Ulrich Gerland

Publications and source records attributed to Ulrich Gerland.

14 recordsLinked to original sources

PubMed2006

Kinetic accessibility of buried DNA sites in nucleosomes.

Using a theoretical model for spontaneous partial DNA unwrapping from histones, we study the transient exposure of protein-binding DNA sites within nucleosomes. We focus on the functional dependence of the rates for site exposure and reburial on the site position, which is measurable experimentally and pertinent to gene regulation. We find the dependence to be roughly described by a random walker model. Close inspection reveals a surprising physical effect of flexibility-assisted barrier crossing, which we characterize within a toy model, the "semiflexible Brownian rotor."

Biophysics↗

PubMed2006

Intermediate phase in DNA melting.

We predict a temperature-driven phase transition of DNA below the melting transition. The additional, intermediate phase exists for repetitive sequences, when the two strands have different lengths. In this phase, the excess bases of the longer strand are completely absorbed as bulge loops inside the helical region. When the temperature is lowered, the excess bases desorb into overhanging ends, resulting in a contour length change. This continuous transition is in many aspects analogous to Bose-Einstein condensation. When the sequence is weakly disordered, the contour length changes discontinuously with temperature.

Base Sequence↗

PubMed2005

Coupled dynamics of RNA folding and nanopore translocation.

The translocation of structured RNA or DNA molecules through narrow pores necessitates the opening of all base pairs. Here, we study the interplay between the dynamics of translocation and base pairing theoretically, using kinetic Monte Carlo simulations and analytical methods. We find that the transient formation of base pairs that do not occur in the ground state can significantly speed up translocation.

Base Pairing↗

PubMed2005

DNA as a programmable viscoelastic nanoelement.

The two strands of a DNA molecule with a repetitive sequence can pair into many different basepairing patterns. For perfectly periodic sequences, early bulk experiments of Pörschke indicate the existence of a sliding process, permitting the rapid transition between different relative strand positions. Here, we use a detailed theoretical model to study the basepairing dynamics of periodic and nearly periodic DNA. As suggested by Pörschke, DNA sliding is mediated by basepairing defects (bulge loops), which can diffuse along the DNA. Moreover, a shear force f on opposite ends of the two strands yields a characteristic dynamic response: An outward average sliding velocity v approximately 1/N is induced in a double strand of length N, provided f is larger than a threshold fc. Conversely, if the strands are initially misaligned, they realign even against an external force f < fc. These dynamics effectively result in a viscoelastic behavior of DNA under shear forces, with properties that are programmable through the choice of the DNA sequence. We find that a small number of mutations in periodic sequences does not prevent DNA sliding, but introduces a time delay in the dynamic response. We clarify the mechanism for the time delay and describe it quantitatively within a phenomenological model. Based on our findings, we suggest new dynamical roles for DNA in artificial nanoscale devices. The basepairing dynamics described here is also relevant for the extension of repetitive sequences inside genomic DNA.

Base Pairing↗

PubMed2005

Nonlinear protein degradation and the function of genetic circuits.

The functions of most genetic circuits require a sufficient degree of cooperativity in the circuit components. Although mechanisms of cooperativity have been studied most extensively in the context of transcriptional initiation control, cooperativity from other processes involved in the operation of the circuits can also play important roles. In this work, we examine a simple kinetic source of cooperativity stemming from the nonlinear degradation of multimeric proteins. Ample experimental evidence suggests that protein subunits can degrade less rapidly when associated in multimeric complexes, an effect we refer to as "cooperative stability." For dimeric transcription factors, this effect leads to a concentration-dependence in the degradation rate because monomers, which are predominant at low concentrations, will be more rapidly degraded. Thus, cooperative stability can effectively widen the accessible range of protein levels in vivo. Through theoretical analysis of two exemplary genetic circuits in bacteria, we show that such an increased range is important for the robust operation of genetic circuits as well as their evolvability. Our calculations demonstrate that a few-fold difference between the degradation rate of monomers and dimers can already enhance the function of these circuits substantially. We discuss molecular mechanisms of cooperative stability and their occurrence in natural or engineered systems. Our results suggest that cooperative stability needs to be considered explicitly and characterized quantitatively in any systematic experimental or theoretical study of gene circuits.

Bacteria↗

PubMed2005

Transcriptional regulation by the numbers: applications.

With the increasing amount of experimental data on gene expression and regulation, there is a growing need for quantitative models to describe the data and relate them to their respective context. Thermodynamic models provide a useful framework for the quantitative analysis of bacterial transcription regulation. This framework can facilitate the quantification of vastly different forms of gene expression from several well-characterized bacterial promoters that are regulated by one or two species of transcription factors; it is useful because it requires only a few parameters. As such, it provides a compact description useful for higher-level studies (e.g. of genetic networks) without the need to invoke the biochemical details of every component. Moreover, it can be used to generate hypotheses on the likely mechanisms of transcriptional control.

Animals↗

PubMed2005

Transcriptional regulation by the numbers: models.

The expression of genes is regularly characterized with respect to how much, how fast, when and where. Such quantitative data demands quantitative models. Thermodynamic models are based on the assumption that the level of gene expression is proportional to the equilibrium probability that RNA polymerase (RNAP) is bound to the promoter of interest. Statistical mechanics provides a framework for computing these probabilities. Within this framework, interactions of activators, repressors, helper molecules and RNAP are described by a single function, the "regulation factor". This analysis culminates in an expression for the probability of RNA polymerase binding at the promoter of interest as a function of the number of regulatory proteins in the cell.

Gene Expression Regulation↗

PubMed2004

Dynamics of force-induced DNA slippage.

We study the base pairing dynamics of DNA with repetitive sequences where local strand slippage can create, annihilate, and move bulge loops. Using an explicit theoretical model, we find a rich dynamical behavior as a function of an applied shear force f: reptationlike dynamics at f=f(c) with a rupture time tau scaling as N3 with its length N, drift-diffusion dynamics for f(c)<f<f(*), and a dynamical transition to an unraveling mode of strand separation at f=f(*). We predict a viscoelastic behavior for periodic DNA with time and force scales that can be programmed into its sequence.

Base Pairing↗

PubMed2004

Translocation of structured polynucleotides through nanopores.

We investigate theoretically the translocation of structured RNA/DNA molecules through narrow pores which allow single but not double strands to pass. The unzipping of basepaired regions within the molecules presents significant kinetic barriers for the translocation process. We show that this circumstance may be exploited to determine the full basepairing pattern of polynucleotides, including RNA pseudoknots. The crucial requirement is that the translocation dynamics (i.e. the length of the translocated molecular segment) needs to be recorded as a function of time with a spatial resolution of a few nucleotides. This could be achieved, for instance, by applying a mechanical driving force for translocation and recording force-extension curves (FECs) with a device such as an atomic force microscope or optical tweezers. Our analysis suggests that, with this added spatial resolution, nanopores could be transformed into a powerful experimental tool to study the folding of nucleic acids.

Animals↗

PubMed2003

On schemes of combinatorial transcription logic.

Cells receive a wide variety of cellular and environmental signals, which are often processed combinatorially to generate specific genetic responses. Here we explore theoretically the potentials and limitations of combinatorial signal integration at the level of cis-regulatory transcription control. Our analysis suggests that many complex transcription-control functions of the type encountered in higher eukaryotes are already implementable within the much simpler bacterial transcription system. Using a quantitative model of bacterial transcription and invoking only specific protein-DNA interaction and weak glue-like interaction between regulatory proteins, we show explicit schemes to implement regulatory logic functions of increasing complexity by appropriately selecting the strengths and arranging the relative positions of the relevant protein-binding DNA sequences in the cis-regulatory region. The architectures that emerge are naturally modular and evolvable. Our results suggest that the transcription regulatory apparatus is a "programmable" computing machine, belonging formally to the class of Boltzmann machines. Crucial to our results is the ability to regulate gene expression at a distance. In bacteria, this can be achieved for isolated genes via DNA looping controlled by the dimerization of DNA-bound proteins. However, if adopted extensively in the genome, long-distance interaction can cause unintentional intergenic cross talk, a detrimental side effect difficult to overcome by the known bacterial transcription-regulation systems. This may be a key factor limiting the genome-wide adoption of complex transcription control in bacteria. Implications of our findings for combinatorial transcription control in eukaryotes are discussed.

Bacteria↗

PubMed2003

Dynamics of competitive evolution on a smooth landscape.

We study competitive DNA sequence evolution directed by in vitro protein binding. The steady-state dynamics of this process is well described by a shape-preserving pulse which decelerates and eventually reaches equilibrium. We explain this dynamical behavior within a continuum mean-field framework. Analytical results obtained on the motion of the pulse agree with simulations. Furthermore, finite population correction to the mean-field results are found to be insignificant.

Binding, Competitive↗

PubMed2003

Mechanically probing the folding pathway of single RNA molecules.

We study theoretically the denaturation of single RNA molecules by mechanical stretching, focusing on signatures of the (un)folding pathway in molecular fluctuations. Our model describes the interactions between nucleotides by incorporating the experimentally determined free energy rules for RNA secondary structure, whereas exterior single-stranded regions are modeled as freely jointed chains. For exemplary RNA sequences (hairpins and the Tetrahymena thermophila group I intron), we compute the quasiequilibrium fluctuations in the end-to-end distance as the molecule is unfolded by pulling on opposite ends. Unlike the average quasiequilibrium force-extension curves, these fluctuations reveal clear signatures from the unfolding of individual structural elements. We find that the resolution of these signatures depends on the spring constant of the force-measuring device, with an optimal value intermediate between very rigid and very soft. We compare and relate our results to recent experiments by Liphardt et al. (2001).

Animals↗

PubMed2002

Physical constraints and functional characteristics of transcription factor-DNA interaction.

We study theoretical "design principles" for transcription factor (TF)-DNA interaction in bacteria, focusing particularly on the statistical interaction of the TFs with the genomic background (i.e., the genome without the target sites). We introduce and motivate the concept of programmability, i.e., the ability to set the threshold concentration for TF binding over a wide range merely by mutating the binding sequence of a target site. This functional demand, together with physical constraints arising from the thermodynamics and kinetics of TF-DNA interaction, leads us to a narrow range of "optimal" interaction parameters. We find that this parameter set agrees well with experimental data for the interaction parameters of a few exemplary prokaryotic TFs, which indicates that TF-DNA interaction is indeed programmable. We suggest further experiments to test whether this is a general feature for a large class of TFs.

Bacterial Proteins↗

PubMed2002

On the selection and evolution of regulatory DNA motifs.

The mutation and selection of regulatory DNA sequences are presented as an ideal model system of molecular evolution where genotype, phenotype, and fitness can be explicitly and independently characterized. In this theoretical study, we construct an explicit model for the evolution of regulatory sequences, making use of the known biophysics of the binding of regulatory proteins to DNA sequences, under the assumption that fitness of a sequence depends only on its binding affinity to the regulatory protein. The model is confined to the mean field (i.e., infinite population size) limit. Using realistic values for all parameters, we determine the minimum fitness advantage needed to maintain a binding sequence, demonstrating explicitly the "error threshold" below which a binding sequence cannot survive the accumulated effect of mutation over long time. The commonly observed "fuzziness" in binding motifs arises naturally as a consequence of the balance between selection and mutation in our model. In addition, we devise a simple model for the evolution of multiple binding sequences in a given regulatory region. We find the number of evolutionarily stable binding sequences to increase in a step-like fashion with increasing fitness advantage, if multiple regulatory proteins can synergistically enhance gene transcription. We discuss possible experimental approaches to resolve open questions raised by our study.

Binding Sites↗